The general objective of this project is to define the mechanisms by which human lymphoid cells interact with antigen-presenting cells in order to produce and regulate immune responses. Over the past year, there have been three major efforts underway that are targeted on this objective: 1) dissection of the molecular basis for T cell recognition of antigens presented by HLA class I molecules; 2) determination of endogenous versus exogenous antigen presentation pathways for class I and II HLA molecules; and 3) analysis of the potential roles of human T cell receptor (TCR) alpha and beta chain germline genes and HLA genes in susceptibility to multiple sclerosis (MS). The principle findings are as follows: 1) two different class I molecules, HLA-A2.1 and HLA-B37, bind largely nonoverlapping sets of peptides; 2) the kinetics of peptide binding to HLA-A2 and the conformation of the peptide-A2 complex can be determined by amino acid side chains on the floor of the peptide binding groove; 3) class II HLA molecules can use the endogenous pathway of antigen presentation; and 4) in certain families that have multiple members with MS, TCR and/or HLA genes can be shown to be associated with susceptibility to MS.